Autologous stem cell transplantation for multiple myeloma (MM) results in effective cytoreduction but patients subsequently relapse. A promising area of investigation is the development of cancer vaccines that educate host immunity to selectively target and eliminate MM cells and can be used to eradicate residual disease following autologous stem cell transplantation. We have developed a cancer vaccine in which dendritic cells (DC) are fused to autologous tumor cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response. In a clinical trial of patients with advanced MM, vaccination with autologous DC/MM fusions induced anti-tumor immunity in a majority of patients, and disease stabilization ranging from 10 weeks to 36 months. In an ongoing trial of MM patients undergoing DC/tumor fusion vaccination in conjunction with stem cell transplantation, we have demonstrated a marked expansion of myeloma reactive T cells with the concomitant eradication of post-transplant residual disease following vaccination. To overcome the intrinsic immunosuppressive environment and regulatory T ceils that limit vaccine response, we are developing strategies to incorporate adoptive immunotherapy with MM reactive T cell clones. One approach is the use of vaccination prior to stem cell collection such that educated lymphocytes are infused at the time of transplant and further expanded in vivo by post-transplant vaccination. Alternatively, adoptive immunotherapy may be further optimized by ex-vivo generation of MM specific T cells with an activated phenotype. We have found that ligation of CD3/CD28 following ex vivo stimulation with DC/MM fusion vaccine results in the dramatic expansion of activated tumor reactive T cells while minimizing the presence of regulatory T cells. Our hypothesis is that combining transplant mediated cytoreduction and regulatory T cell depletion with the infusion of activated tumor reactive lymphocytes and boosting vaccination with DC/MM fusions offers the ideal platfomn for optimized cellular immunotherapy in MM. To address this hypothesis the Specific Aims are: 1) To evaluate toxicity, cellular and humoral antitumor immunity, and clinical response of a combined DC/MM vaccination and adoptive transfer of in vivo primed T cells; 2) To optimize strategies for the ex vivo expansion of myeloma specific T cells using sequential stimulation with DC/MM fusions and anti-CD3/CD28 ex vivo; and 3) To define the toxicity, immunologic response and clinical effect of ex vivo generated and expanded myeloma specific T cells administered in conjunction with pre and post-transplant vaccination with DC/MM fusions.